Antimalarial activity and sensitization of chrysosplenetin against artemisinin‐resistant genotype Plasmodium bergheiK173 potentially via dual‐mechanism of maintaining host P‐glycoprotein homeostasis mediated by NF‐κB p52 or PXR/CAR signaling pathways and regulating heme/haemozoin metabolism

Abstract

This study investigated antimalarial efficacy and sensitization of chrysosplenetin against artemisinin‐resistant Plasmodium berghei K173 and potential molecular mechanism. Our data indicated a risk of artemisinin resistance because a higher parasitaemia% and lower inhibition% under artemisinin treatment against resistant parasites than those in the sensitive groups were observed. Two non‐antimalarial components, verapamil and chrysosplentin, being P‐gp inhibitors, possessed a strong efficacy against resistant parasites but it was not the case for Bcrp inhibitor novobiocin. Artemisinin‐chrysosplenetin combination improved artemisinin susceptibility of resistant P. berghei. Artemisinin activated intestinal P‐gp and Abcb1/Abcg2 expressions and suppressed Bcrp whereas chrysosplenetin reversed them. Resistant parasite infection led to a decreased haemozoin in organs or an increased heme in peripheral bloods compared with the sensitives; however, that in Abcb1‐deficient knockout (KO)‐resistant mice reversely got increased or decreased versus wild type (WT)‐resistant animals. Chrysosplenetin as well as rifampin (nuclear receptor agonist) increased the transcription levels of PXR/CAR while showed a versatile regulation on hepatic and enternal PXR/CAR in WT‐ or KO‐sensitive or ‐resistant parasites. Oppositely, hepatic and enteric NF‐κB p52 mRNA decreased conformably in WT but increased in KO‐resistant mice. NF‐κB pathway potentially involved in the mechanism of chrysosplenetin on inhibiting P‐gp expressions while PXR/CAR play a more complicated role in this mechanism.